Otitis media (OM), the most common pediatric disease, is recognized to be multifactorial, with complex genetic, environmental and infectious etiologies. Acute otitis media (AOM) usually occurs as a bacterial complication of viral upper respiratory tract infection (URI) in children. Evidence suggests that different types of viruses vary in their ability to induce AOM. The long-term objectives of our research group are to elucidate the contribution of viruses, bacteria and their complex interactions in the pathogenesis of and recovery from AOM, and to identify possible strategies for more effective prevention and/or treatment. The proposed 5-year study will investigate the relationship between "host" and "microbe" in the development of virus-induced AOM. We will explore the pathogenicity of specific respiratory viruses, and the role of proinflammatory cytokines (TNFcx, -IL-1B, IL-6) and their gene regulation in the mechanisms of virus-induced AOM. In Aim 1, we will study differential cytokine expression in virus-induced AOM in vivo and in vitro. We will prospectively follow 210 infants and children, with and without polymorphisms of acute phase cytokine genes (TNFcx(-308, IB-+3953, and IL- 6 alleles) for one year. For 3 weeks after each viral URI episode, we will monitor for the occurrence of AOM. We will compare virus type and cytokine concentrations in respiratory secretions from children who do and who do not develop AOM as a complication. Risk for AOM development will be evaluated for association with cytokine genotypes. In the in vitro experiments, induction of cytokine production by specific viruses will be studied in peripheral blood mononuclear leukocytes from healthy adult volunteers with normal or polymorphic cytokine genes. Aim 2 will retrospectively evaluate the association between polymorphisms of proinflammatory cytokine genes and susceptibility to OM, using peripheral blood from 200 children with and without a history of recurrent OM. These studies will clarify the role of specific respiratory viruses, proinflammatory cytokines, and their gene regulation in the pathogenetic mechanisms of virus-induced AOM. Study results should improve risk identification for recurrent OM in the population, which may facilitate specific prophylactic and therapeutic approaches for the high risk groups. The study will also lay the ground work for the future design of innovative approaches to prevent or reduce morbidity of AOM, such as therapies using specifically targeted viral vaccines, antiviral drugs, and immunomodulators.